Synthesis of methyl 2-((2-(cyclohexylamino)-2-oxo-1-phenylethyl) amino)benzoate

Reaction between substituted benzaldehydes, anthranilic acid, and cyclohexyl isocyanide gave rise to pure methyl 2-((2-(cyclohexylamino)-2-oxo-1-phenylethyl) amino)benzoates, that can be useful to design new drugs.


Introduction
The synthesis of molecules with high diversity and complexity using readily available starting materials is an interesting approach in combinatorial chemistry and drug discovery.
In this regard, combining the multicomponent reactions MCRs has been used as an efficient method for the synthesis of highly functionalized compounds. 17][8] Recently, a new version of the isocyanide-based Ugi three-component coupling reaction (3CC) using an aldehyde and acid has been developed as a bi-functional substrate. 9,10Intermolecular versions of the Ugi reaction have also been reported, where two of the four functional groups are present in the same molecule.The possibility of generating heterocyclic molecules using bi-functional compounds is known as the Ugi-4-centre-3-component reaction (U-4C-3CR). 11,12mong the various bioactive heterocyclic molecules, N-substituted anthranilic acid derivatives have been the object of intense studies because of their biological activities and therapeutic applications. 13Mefenamic acid and meclofenamates 14 both are N-phenylanthranilic acid derivatives, which have been used as antiinflammatory agents in treatments.A considerable amount of work has been done on the structural variation of this subclass of drugs broadly known as non-steroidal anti-inflammatory drugs (NSAIDs).It has been observed that the best known NSAIDs are in form acidic.In this regard, our attention has been directed to the variation at position-2 of anthranilic acid with a view to synthesize new analogies with improved antiinflammatory effects.Recent literatures show that substitutions at 2-position of anthranilic acid (2-amino benzoic acid) by different substituted aryl or heteroaryl moieties markedly modulate the anti-inflammatory activity. 15,16s part of our program is aimed at developing new isocyanide-based multi-component reactions for the synthesis of heterocycles, herein we report a new efficient synthesis of methyl 2-((2-(cyclohexylamino)-2-oxo-1-phenylethyl)amino)benzoate via Ugi reaction.
The effect of different solvents on the reaction was also examined, and the results are summarized in Scheme 1.We found in absolute ethanol, the desired product was obtained in 90% yield while in methanol, 5f was isolated in 98% yield (Scheme 1).When the water content in the reaction mixture was increased, the yield of the target molecule dropped, and using water as the solvent gave very low yields.According to the attack of nucleophilic solvents at the carbonyl group in the β-lactam skeleton we carried out this reaction in THF and CH3CN as non-nucleophilic solvents under the same conditions (Scheme 1).In these solvents the desired product was not formed.On the basis of this information, 5f was produced in higher yields using methanol solvent much higher in comparison with that of ethanol; therefore, we chose the MeOH for this transformation because of cost and environmental concerns.
This result provided an incentive for further study, to consider anthranilic acid and different aromatic aldehydes and isocyanide.Interestingly, substituted aromatic aldehydes with electron-withdrawing groups such as, p-bromo, p-chloro, m-chloro, p-nitro, m-nitro derivatives and substituted aromatic aldehydes with electron-donating groups such as p-methyl, p-methoxy each participated effectively in this reaction.In all the cases, the reactions were clean and provided the desired methyl 2-((2-(cyclohexylamino)-2-oxo-1-phenylethyl) amino)benzoate derivatives in high yields.The Ugi-adduct was purified by chromatography to result in the production of 5a-l.All products were fully characterized and confirmed by NMR, IR and elemental analysis.The scope and generality of this process is illustrated with respect to anthranilic acid and different aromatic aldehydes (Table 1).
A plausible mechanism for this reaction is shown in scheme 2. We assume that the reaction proceeds via the initial formation of imine (A) which is formed in situ from the aromatic aldehyde and anthranilic acid.The imine intermediate is attacked by the nucleophilic isocyanide, followed by abstraction of a proton from the carboxylic acid leading to formation of nitrilium carboxylate (B).The subsequent attack of the carboxylate anion on the nitrilium ion generates the cyclic intermediate (C), which undergoes a Mumm rearrangement to give the desired lactam 4 and finally nucleophilic attack of methanol on the carbonyl group of lactam 4 affords the product 5 (Scheme 2).Scheme 2. A plausible reaction pathway.